Pathological interactions of a-syn, mitochondria, and pesticides in PD models

描述（由申请方提供）：帕金森病（PD）是一种常见的迟发性、进行性神经退行性疾病，其特征为皮质下神经元群变性，包括黑质、丘脑部（SNpc）的多巴胺能神经元，以及存在由α-突触核蛋白组成的细胞质内含物。虽然PD的原因尚不清楚，但α-突触核蛋白的遗传和生化异常直接涉及PD和其他α-突触核蛋白病的发病机制。α-突触核蛋白异常和神经变性之间的因果关系由各种遗传模型显示，其中α-突触核蛋白异常导致具有神经变性的成人发作的神经系统疾病。一些模型表现出人类α-突触核蛋白病的许多特征，包括α-突触核蛋白的异常聚集和皮质下区域的神经变性。我们的研究表明tg小鼠的α-突触核蛋白病与氧化应激和线粒体异常有关。由于线粒体异常和氧化应激都与PD和其他α-突触核蛋白病的发病机制有关，我们将在Hua-Syn Tg小鼠和细胞模型中检查线粒体功能障碍、氧化应激和α-突触核蛋白病之间的病理关系（目的1和2）。此外，我们的研究表明，α-突触核蛋白转基因小鼠对慢性MPTP治疗诱导的神经退行性变的易感性增加。因此，α-突触核蛋白、环境因素（如杀虫剂）引起的线粒体功能障碍和神经退行性变之间可能存在直接的病理联系。我们将使用已知抑制复合物I活性的杀虫剂，使用细胞培养（Aim 3）和转基因小鼠模型（Aim 4）来定义这些已知PD风险因素的因素之间的病理相互作用。这些研究将提供与人类α-突触核蛋白病的发病机制直接相关的过程的体内实验测试，并可能导致新的治疗方法。 公共卫生相关性：帕金森病和相关的α-突触核蛋白病是致命的神经退行性疾病，在美国每年影响约1，000，000人。研究表明，PD与α-突触核蛋白异常、线粒体功能障碍和农药暴露有关。我们将确定内在（α-突触核蛋白）和外在（环境毒素）因素如何在病理上影响线粒体功能并导致神经退行性变。我们的发现将导致更好地了解PD和治疗干预的新靶点。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a common late onset, progressive neurodegenerative disease characterized by degeneration of subcortical neuronal populations, including dopaminergic neurons of substantia nigra, pars compacta (SNpc), and presence of the cytoplasmic inclusions composed of alpha-synuclein. While the causes of PD are not known, genetic and biochemical abnormalities of alpha-synuclein are directly implicated in the pathogenesis of PD and other alpha-synucleinopathies. Causal link between alpha-synuclein abnormalities and neurodegeneration is shown by various genetic models where alpha-synuclein abnormalities lead to adult- onset neurological disease with neurodegeneration. Some models exhibit many of the features of human alpha-synucleinopathies, including aberrant aggregation of alpha-synuclein and neurodegeneration in subcortical regions. Our studies indicate that alpha-synucleinopathy in tg mice is associated with oxidative stress and mitochondrial abnormalities. Because both mitochondrial abnormalities and oxidative stress are implicated in the pathogenesis of PD and other a-synucleinopathies, we will examine the pathological relationships between mitochondrial dysfunction, oxidative stress and alpha-synucleinopathies in Hua-Syn Tg mice and in cell models (Aims 1 and 2). In addition, our studies show that alpha-synuclein transgenic mice exhibit increased vulnerability to neurodegeneration induced by the chronic MPTP treatment. Thus, there could be a direct pathologic link between alpha-synuclein, mitochondrial dysfunction via environmental agents (such as pesticides), and neurodegeneration. We will use pesticides that are known to inhibit complex I activity to define the pathological interactions between these factors that known risk factors for PD using cell culture (Aim 3) and transgenic mouse models (Aim 4). These studies will provide in vivo experimental tests of processes that are directly relevant to the pathogenesis of human alpha-synucleinopathies and may lead to new therapeutic approaches. PUBLIC HEALTH RELEVANCE: Parkinson's disease and related alpha-synucleinopathies are fatal neurodegenerative diseases affecting ~1,000,000 individuals annually in US. Studies indicate that PD is associated with alpha-synuclein abnormalities, mitochondrial dysfunction, and pesticide exposure. We will determine how intrinsic (alpha- synuclein) and extrinsic (environmental toxins) factors act in concert of pathologically affect mitochondrial function and lead to neurodegeneration. Our finding will lead to better understanding of PD and new targets for therapeutic intervention.